Mechanisms influencing stimulatory effects of spermine at recombinant N-methyl-D-aspartate receptors.

Stimulatory effects of spermine at heteromeric N-methyl-D-aspartate (NMDA) receptors expressed from cloned subunits were studied by voltage-clamp recording in Xenopus oocytes. At NR1A/NR2B receptors, in the presence of a saturating concentration of glycine, the magnitude of spermine stimulation was dependent on the concentration of NMDA or glutamate. In oocytes voltage-clamped at -25 mV, spermine markedly enhanced the response to 10 microM NMDA but had little or no effect on the response to 10 microM NMDA. This effect was not related to the size of the macroscopic currents, the quantity or ratio of injected receptor subunit RNAs, or a voltage-dependent block by spermine. Spermine induced a small (1.2-1.5-fold) decrease in the affinity of NR1A/NR2B receptors for NMDA and glutamate. This decrease was sufficient to counteract the stimulatory effect of spermine at low concentrations of NMDA and glutamate, resulting in no net effect of spermine or a decrease in macroscopic currents in the presence of spermine with low concentrations of agonist. Spermine did not alter the affinity of NR1A/NR2A receptors for NMDA. Endogenous polyamines could act as a bidirectional gain control at some native NMDA receptors containing the NR1A and NR2B subunits, by dampening the response to low concentrations of glutamate and enhancing the response to high concentrations of glutamate. Alternatively, polyamines could enhance the decay of NMDA receptor-mediated responses by increasing the rate of dissociation of glutamate from the receptor.